Acylguanidine inhibitors of beta -secretase: Optimization of the pyrrole ring substituents extending into the S sub(1) and S sub(3) substrate binding pockets

Proteolytic cleavage of amyloid precursor protein by beta -secretase (BACE- 1) and gamma -secretase leads to formation of beta -amyloid (A beta ) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5- diphenyl-pyrrol-1-yl)-acetyl]guanidine ( 3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S sub(1) and S sub(2') pockets leading to submicromolar BACE-1 inhibitors.